Comparative study of the effects of four cephalosporins against Escherichia coli in vitro and in vivo.
A thigh muscle infection induced with Escherichia coli in irradiated mice was used as a model to compare the in vivo pharmacodynamics of the antibacterial effect of four cephalosporins (i.e., cefepime, ceftriaxone, ceftazidime, and cefoperazone) with the in vitro antibacterial pharmacodynamics of these drugs. The following in vitro pharmacodynamic parameters were determined: the maximum effect as a measure for efficacy, the 50% effective concentration as a parameter for potency, and the slope of the concentration-effect relationship. For analysis of the in vivo antibacterial pharmacodynamics, the same parameters were applied for the dose instead of the concentration. For the detection of a relationship between concentration and antibacterial effect in vivo, we determined the pharmacokinetics of the four cephalosporins in the plasma of mice. The results showed that, in general, there is a direct relationship between the in vivo and in vitro pharmacodynamics of these cephalosporins. The maximum effects of cefepime, ceftazidime, and cefoperazone were approximately similar in vivo and in vitro. The sequence of potency of these drugs was, in descending order, cefepime, ceftazidime, and cefoperazone. Ceftriaxone differed from the other three cephalosporins in that it displayed unexpected in vivo pharmacodynamics. Ceftriaxone was just as efficacious as the other three in vitro, but its maximum effect in vivo was much lower. This relatively low maximum effect of ceftriaxone in vivo was not explained by the pharmacokinetic characteristics of the drug. From the present results it can be concluded that the in vitro efficacy of cephalosporins does not necessarily have a predictive value for the in vivo efficacy.
van Ogtrop
M L
ML
Department of Infectious Diseases, University Hospital, Leiden, The Netherlands.
Mattie
H
H
Guiot
H F
HF
van Strijen
E
E
Hazekamp-van Dokkum
A M
AM
van Furth
R
R
D000818:Animals; D000077723:Cefepime; D002438:Cefoperazone / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002442:Ceftazidime / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002443:Ceftriaxone / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002511:Cephalosporins / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli / Q000187:drug effects / Q000254:growth & development; D004927:Escherichia coli Infections / Q000188:drug therapy*; D005260:Female; D051379:Mice
D002511:Cephalosporins; D002443:Ceftriaxone; D002438:Cefoperazone; D000077723:Cefepime; D002442:Ceftazidime